INSERM U976, Hôpital Saint Louis, Paris, France.
Nat Struct Mol Biol. 2011 May;18(5):584-91. doi: 10.1038/nsmb.2022. Epub 2011 Apr 10.
Melanocytes use BRAF to activate the MAP kinase (MAPK) pathway because CRAF is inhibited by the cyclic AMP (cAMP) pathway in these cells. By contrast, melanomas harboring Ras mutations use CRAF to activate the MAPK pathway. We describe the molecular mechanism of Raf isoform switching and cAMP pathway disruption, which take place during melanocyte transformation. We show that overactivation of the MAPK pathway, induced by the oncogenic Ras in melanoma, induces constitutive phosphorylation of BRAF on Ser151 by ERK, which inhibits NRAS-BRAF interaction . We also demonstrate that melanoma cells have elevated cAMP phosphodiesterase activity owing to overexpression of the cAMP-specific phosphodiesterase-4 enzymes; this activity inhibits cAMP signaling and allows CRAF reactivation in these cells. Reactivating the cAMP pathway inhibits proliferation and induces apoptosis of Ras-mutated melanoma cells, suggesting a new therapeutic approach for treating melanomas harboring Ras mutations.
黑素细胞使用 BRAF 激活 MAP 激酶（MAPK）通路，因为在这些细胞中，CRAF 被环腺苷酸（cAMP）通路抑制。相比之下，携带 Ras 突变的黑色素瘤使用 CRAF 激活 MAPK 通路。我们描述了 Raf 同工型转换和 cAMP 通路中断的分子机制，这些机制发生在黑素细胞转化过程中。我们表明，黑色素瘤中致癌 Ras 诱导的 MAPK 通路过度激活，导致 ERK 对 BRAF 的 Ser151 进行组成性磷酸化，从而抑制 NRAS-BRAF 相互作用。我们还证明，黑色素瘤细胞由于 cAMP 特异性磷酸二酯酶-4 酶的过度表达而具有升高的 cAMP 磷酸二酯酶活性；这种活性抑制 cAMP 信号转导，并允许 CRAF 在这些细胞中重新激活。激活 cAMP 通路抑制 Ras 突变黑色素瘤细胞的增殖并诱导其凋亡，提示了一种治疗携带 Ras 突变的黑色素瘤的新治疗方法。
